What is the mechanism of action (MOA) of Oral Antidiabetic Drugs (OAD) in adults with type 2 diabetes mellitus (T2DM)?

Mechanisms of Action of Oral Antidiabetic Drugs

Oral antidiabetic drugs (OADs) work through five distinct mechanisms targeting different pathophysiologic defects in type 2 diabetes: enhancing insulin sensitivity, stimulating insulin secretion, slowing carbohydrate absorption, inhibiting renal glucose reabsorption, and potentiating incretin effects. 1

Primary Mechanisms by Drug Class

Biguanides (Metformin)

• Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. 2
• Metformin improves insulin sensitivity primarily in the liver and muscle tissue without directly affecting β-cell function. 1
• Insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease. 2
• This mechanism addresses the elevated basal hepatic glucose production that is the primary cause of fasting hyperglycemia in type 2 diabetes. 1, 3

Thiazolidinediones (Pioglitazone, Rosiglitazone)

• Thiazolidinediones decrease insulin resistance in the periphery and in the liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. 4
• These agents are potent agonists for peroxisome proliferator-activated receptor-gamma (PPARγ), which modulates transcription of insulin-responsive genes involved in glucose and lipid metabolism. 4
• Thiazolidinediones improve peripheral insulin sensitivity by acting as insulin sensitizers in muscle and adipose tissue. 1
• Unlike sulfonylureas, pioglitazone is not an insulin secretagogue and enhances the effects of circulating insulin by decreasing insulin resistance. 4
• The metabolic changes result in increased responsiveness of insulin-dependent tissues and do not lower blood glucose in models lacking endogenous insulin. 4

Sulfonylureas and Meglitinides (Glinides)

• These agents enhance insulin secretion from pancreatic β-cells. 5, 6
• Sulfonylureas are classified as hypoglycemic agents because they directly stimulate insulin release. 6
• This mechanism addresses impaired insulin secretion, one of the two major defects in type 2 diabetes. 3

Alpha-Glucosidase Inhibitors

• Alpha-glucosidase inhibitors slow the hydrolysis of complex carbohydrates in the small intestine, thereby slowing carbohydrate absorption. 1
• These agents inhibit intestinal carbohydrate absorption and are classified as antihyperglycemic rather than hypoglycemic agents. 5, 6
• This mechanism specifically targets postprandial hyperglycemia by reducing the rate of glucose absorption. 3

DPP-4 Inhibitors

• Dipeptidyl peptidase-4 (DPP-4) inhibitors potentiate the activity of the incretin glucagon-like peptide-1 (GLP-1) and enhance glucose-dependent insulin secretion. 5
• These agents work through a complementary mechanism of action by preserving endogenous incretin hormones. 7
• DPP-4 inhibitors offer glycemic control without hypoglycemia or weight gain. 5

SGLT-2 Inhibitors

• Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are mainly expressed in S1 and S2 segments of the proximal convoluted tubule in the kidneys, preventing renal glucose reabsorption and increasing glycosuria. 8
• This represents a novel insulin-independent mechanism for glucose lowering. 8
• SGLT-2 inhibitors work through the kidneys rather than targeting insulin resistance or secretion directly. 8

Pathophysiologic Context

• Type 2 diabetes results from defects in both insulin secretion and insulin action, with elevated basal hepatic glucose production in the presence of hyperinsulinemia being the primary cause of fasting hyperglycemia. 1, 3
• After meals, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia. 3
• The UKPDS demonstrated that improved glycemic control, irrespective of the agent used, decreased microvascular complications by 25%. 1

Clinical Selection Based on Mechanism

• Metformin is recommended as first-line treatment because it addresses the primary defect of excessive hepatic glucose production without causing hypoglycemia. 8
• When a second oral therapy is needed, clinicians should consider adding either a sulfonylurea, thiazolidinedione, SGLT-2 inhibitor, or DPP-4 inhibitor to metformin based on complementary mechanisms of action. 8
• Selection among second-line agents should account for their different mechanisms: sulfonylureas enhance insulin secretion, thiazolidinediones improve peripheral insulin sensitivity, SGLT-2 inhibitors increase urinary glucose excretion, and DPP-4 inhibitors enhance incretin effects. 8, 7, 5

Important Caveats

• In advanced chronic kidney disease, decreased insulin clearance and reduced gluconeogenesis alter the effectiveness and safety profile of oral hypoglycemic agents. 1
• Patients with end-stage kidney disease experience decreased insulin degradation, leading to reduced requirements for exogenous insulin and oral agents. 1
• Most patients with type 2 diabetes require combination therapy targeting multiple mechanisms because the disease is progressive and involves multiple pathophysiologic defects. 3, 7